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This Week’s Citation Classic®
CC/NUMBER 36
SEPTEMBER 5,
van Zwieten P A. Antihypertensive drugs with a central action. (Whole issue.)
Prog. Pha.rmacol. 1(1), 1975. 63 p.
(Laboratorium voor Farrnacie, Universiteit van Amsterdam, Afdeling Farmacotherapie.
The Netherlands)
___________________________________
This review paper deals with drugs that lower blood
pressure owing to their effect on the brain centres,
neurones, and adrenoceptors, which are involved in
the central nervous system regulation of blood pressure and heart rate. Clonidine, guanfacine, and amethyl-DOPA (which is converted ri the brain into
a-methylnoradrenalirte) are the prototypes of the
centrally acting antihypertensives. Theystimulate central a -adrenoceptors and hence reduce peripheral5
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sympathetic
tone and blood pressure. )The Sd
indicates that this work has been cited in over 245
publications, making it the most-cited paper published
itt this journal.)
P.A. van Zwieten
Division of Pharmacotherapy
Academic Medical Centre
University of Amsterdam
1105 AZ Amsterdam
The Netherlands
February 23, 1988
The recognition that the brain plays an important role in cardiovascular control
prompted the search for drugs that lower
blood pressure via a primary target in the central nervous system. This search was greatly
facilitated by the development ofrefined methods, allowing the injection of small amounts
of the drugs to be tested into the appropriate
brain regions. Circulatory effects of the drugs
after application to the brain can subsequently
be compared quantitatively with effects obtained after injection of the drugs into the systemic circulation. A suitable method for this
purpose, which we developed, is the injection
of drugs into the left thoracic vertebral artery
(VA) of the cat. This method, although technically and surgically more difficult, is preferable to intracarotid administration of drugs,
since the VA predominantly perfuses the
ponto.medullary region of the brain, where the
relevant centers involved in central nervous
cardiovascular control are located.
The basic experimental findings that greatly
stimulated us to perform research on centrally
acting antihypertensives and their mode of action were the following: extremely low doses
of clonidine, guanfacine, or a-methyl-DOPA,
when injected into the VA, caused a pronounced and prolonged fall in arterial blood
pressure, whereas the same or even much
higher doses proved ineffective when applied
to the systemic circulation. The mode of action
of the drugs could be analysed by means of
appropriate agonists and antagonists and may
be summarized as follows: clonidine, guanfacine, and a-methylnoradrenaline (from
o-methyl-DOPA) are agonists towards e-adrenoceptors in the brain stem. The stimulation
of the ta-adrenoceptors involved causes a depression of peripheral sympathetic tone, probably via the activation of a bulbo-spinal neuron. The depressed peripheral sympathetic
tone, as reflected by low plasma catecholamines, readily explains the fall in blood pressure and heart rate caused by the aforementioned drugs. Sedation and dry mouth, the
most common side effects of the centrally acting drugs, are also mediated via a-adrenoceptors, though in other anatomical regions than
those involved in central cardiovascular control.
The concept of central a-adrenoceptors as
the primary target of clonidine and related
drugs also explains the well-known interaction
between these drugs and tricyclic antidepressants. The central hypotensive action of donidine and similarly acting agents, mediated
by a-adrenoceptor stimulation, is diminished
or abolished by various tricyclic antidepressants (imipramine and related compounds) because they are a-adrenoceptor antagonists,
also at the level of the central a-adrenoceptors.
The concept of central a-adrenoceptors as
the basis of central hypotensive activity was
developed simultaneously, and in friendly
competition, by the research 2teams of W.
Kobinger’ (Vienna), H. Schmitt (Paris), and
by us (Amsterdam). Since the publication of
the 1973 review paper many new findings
have been recorded that, however, have not
fundamentally changed the classical concept.
Among the newer findings we would like to
mention: (1) the identification o(the central
a-adrenoceptors as belonging to the a~.sub3
type, probably located at postsynaptic sites~
and (2) a quantitative analysis of the
structure-activity relationship concerning the
agonists that interact with the central a-adrenoceptor, thusallowing
a detailed description
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of the receptor.
I. Kobinger W. CenOal in-adrenergic systems as targets for hypotensive drugs. Ret’. Physic,1. Biochem. Pharmacol. St:39-180,
1978. (Citcd 385 times.) (See also: Kobinger W. Citation Classic. Current Contents/Life Sciences 30(50): Il.
14 December 1987.1
2. Schmitt H. Action des o-sytnpathomiméuques sac les smicrures nerveuses (Effects of o-sympathoosimelics on nerve
structures). Actual. Pha.nnacoi. 24:93-131, 1971. (Cited 65 times.)
3. van Zwleten P A & Timmermans P B M W M. Central and peripheral o-adrenoceplors, pharmacological aspects and
clinical potential. Advan. Drug Ret. 13:209-54, 1984. (Cited 15 times.)
4. Timmermans P B M W M. Hoefke W, StShle H & van Zwieten P A. Structure-activity relationships in clonidine-like
imidazolidines and related compounds. (Whole issue.) Ping. Pt,.annacol. 3(1), 1980. 97 p. (Cited 50 times.l
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